The major component of elastic fibers is an amorphous polymer composed of the polypeptide elastin (known as tropoelastin when in monomeric form). Polymerization of elastic fibers requires an initial step of oxidative deamination of lysine residues, which is catalyzed by a lysyl oxidase (Kagan et al., J. Cell. Biochem. 88, 660-672 (2003)). The resulting aldehyde groups condense spontaneously with adjacent aldehydes or ε-amino groups of peptidyl lysine to form covalent cross-linkages. Lysyl oxidases are copper-dependent monoamine oxidases secreted by fibrogenic cells including fibroblasts and smooth muscle cells. Mammalian genomes have up to five potential LOX family members coding for the prototypic LOX and LOX-like polypeptides 1 through 4 (LOXL1-4) (Kagan et al., supra). Their individual roles in elastogenesis was unclear.
Elastogenesis also requires a scaffolding structure onto which elastin is deposited. Microfibrils, made up of fibrillins and microfibril-associated glycoproteins, are thought to serve as a scaffold which guides elastin deposition (Kielty et al., J. Cell. Sci. 115, 2817-2828 (2002)). However, inactivation of fibrillin 1 and 2 genes individually suggests that each is dispensable for elastogenesis (Pereira et al., Nat. Genet. 17, 218-222 (1997); Chaudhry et al., Hum. Mol. Genet. 10, 835-843 (2001)). Elastin binding protein (EBP) (Hinek et al., J. Cell. Biol. 126, 563-574 (1994)), fibulin-5 (Yanagisawa et al., Nature 415, 168-171 (2002)) and an unspecified lysyl oxidase (Kagan et al., J. Cell. Biol. 103, 1121-1128 (1986)) were also reported to associate with elastic fibers. Gene targeting studies show that fibulin-5 is required for elastic fiber development (Yanagisawa et al., Nature 415, 168-171 (2002); Nakamura et al., Nature 415, 171-175 (2002)). Disruption of the Lox gene leads to a reduction in collagen and elastin cross-links and perinatal lethality (Maki et al., Circulation 106, 2503-2509 (2002); Hornstra et al., J. Biol. Chem. 278, 14387-14393 (2003)), suggesting a role in cross-linking both fibrillar collagens and elastin during development.